For most eukaryotes, sexual reproduction is a fundamental process that requires meiosis. In turn, meiosis typically depends on a reciprocal exchange of DNA between each pair of homologous chromosomes, known as a crossover (CO), to ensure proper chromosome segregation. The frequency and distribution of COs are regulated by intrinsic and extrinsic environmental factors, but much more is known about the molecular mechanisms governing the former compared to the latter. Here we show that elevated temperature induces meiotic hyper-recombination in Arabidopsis thaliana and we use genetic analysis with mutants in different recombination pathways to demonstrate that the extra COs are derived from the major Type I interference sensitive pathway. We also show that heat-induced COs are not the result of an increase in DNA double-strand breaks and that the hyper-recombinant phenotype is likely specific to thermal stress rather than a more generalized stress response. Taken together, these findings provide initial mechanistic insight into how environmental cues modulate plant meiotic recombination and may also offer practical applications.

Chromosome condensation, a process mediated by the condensin complex, is essential for proper chromosome segregation during cell division. Unlike rapid mitotic chromosome condensation, meiotic chromosome condensation occurs over a relatively long prophase I and is unusually complex due to the coordination with chromosome axis formation and homolog interaction. The molecular mechanisms that regulate meiotic chromosome condensation progression from prophase I to metaphase I are unclear. Here, we show that the Arabidopsis thaliana meiotic PHD-finger protein MMD1/DUET is required for progressive compaction of prophase I chromosomes to metaphase I bivalents. The MMD1 PHD domain is required for its function in chromosome condensation and binds to methylated histone tails. Transcriptome analysis and qRT-PCR showed that several condensin genes exhibit significantly reduced expression in mmd1 meiocytes. Furthermore, MMD1 specifically binds to the promoter region of the condensin subunit gene CAP-D3 to enhance its expression. Moreover, cap-d3 mutants exhibit similar chromosome condensation defects, revealing an MMD1-dependent mechanism for regulating meiotic chromosome condensation, which functions in part by promoting condensin gene expression. Together, these discoveries provide strong evidence that the histone reader MMD1/DUET defines an important step for regulating the progression of meiotic prophase I chromosome condensation.

Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the mixed-lineage leukemia (MLL)rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure−activity relationship studies of the hits and structure-based inhibitor design led to two compounds, 11 and 24, with IC 50 values below 100 nM in inhibiting the ENL− acetyl-H3 interaction. Both compounds, and their precursor compound 7, displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.

Meiotic recombination contributes to the maintenance of the association between homologous chromosomes (homologs) and ensures the accurate segregation of homologs during anaphase I, thus facilitating the redistribution of alleles among progeny. Meiotic recombination is initiated by the programmed formation of DNA double strand breaks, the repair of which requires DNA synthesis, but the role of DNA synthesis proteins during meiosis is largely unknown. Here, we hypothesized that the lagging strand-specific DNA Polymerase d (POL d) might be required for meiotic recombination, based on a previous analysis of DNA Replication Factor1 that suggested a role for lagging strand synthesis in meiotic recombination. In Arabidopsis (Arabidopsis thaliana), complete mutation of the catalytic subunit of POL d, encoded by AtPOLD1, leads to embryo lethality. Therefore, we used a meiocyte-specific knockdown strategy to test this hypothesis. Reduced expression of AtPOLD1 in meiocytes caused decreased fertility and meiotic defects, including incomplete synapsis, the formation of multivalents, chromosome fragmentation, and improper segregation. Analysis of meiotic crossover (CO) frequencies showed that AtPOLD1 RNAi plants had significantly fewer interference-sensitive COs than the wild type, indicating that AtPOL d participates in type I CO formation. AtPOLD1 RNAi atpol2a double mutant meiocytes displayed more severe meiotic phenotypes than those of either single mutant, suggesting that the function of AtPOLD1 and AtPOL2A is not identical in meiotic recombination. Given that POL d is highly conserved among eukaryotes, we hypothesize that the described role of POL d here in meiotic recombination likely exists widely in eukaryotes.

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